The world is facing an enormous and growing threat from the emergence of bacteria that are resistant to almost all available antibiotics. Whilst a small number of new antibiotics targeting multidrug-resistant (MDR) Gram-positive bacteria have been approved in the past two decades, there has been a marked decline in the discovery of novel antibiotics for the treatment of Gram-negative bacteria.
Representative genera of Gram-negative bacteria are: Acinetobacter; Actinobacillus; Bartonella; Bordetella; Brucella; Burkholderia; Campylobacter; Cyanobacteria; Enterobacter; Envinia; Escherichia; Francisella; Helicobacter; Hemophilus; Klebsiella; Legionella; Moraxella; Morganella; Neisseria; Pasteurella; Proteus; Providencia; Pseudomonas; Salmonella; Serratia; Shigella; Stenotrophomonas; Treponema; Vibrio; and Yersinia. 
The Infectious Diseases Society of America (IDSA) has placed P. aeruginosa, A. baumannii and K. pneumoniae on a ‘hit list’ of the six top-priority dangerous MDR microorganisms, the so-called ‘superbugs’, in its recent ‘Bad Bugs Need Drugs’ campaign. While the recently approved tigecycline is active against a range of clinically important Gram-negative pathogens, including Acinetobacter baumannii, it is reported to not be effective against Pseudomonas aeruginosa. Numerous hospitals worldwide have experienced outbreaks of infections caused by P. aeruginosa, A. baumannii or K. pneumoniae that are resistant to all commercially available antibiotics, except for the last-line therapy polymyxins.
Polymyxins belong to a class of peptides which was discovered more than 60 years ago. They are produced by nonribosomal biosynthetic enzymes from the secondary metabolic pathways in Paenibacillus polymyxa. There are two polymyxins clinically available, colistin (polymyxin E) and polymyxin B. Commercial preparations of polymyxin B and colistin are mixtures of closely related peptides obtained from fermentation (Orwa, J. A., et al. (2001) J. Chromatography A. 912, 369-373; Govaerts, C., et al. (2002) J. Chromatography A. 976, 65-78). The two major components found in polymyxin B preparations are namely polymyxin B1 and B2, whilst commercial preparations of colistin contain two major components labelled with colistin A and B. The structures of these polymyxin B and colistin components are shown below.

Polymyxins are now being used as a last-line class of antibiotics in patients where all other available antibiotics are inactive. Despite the efficacy of polymyxins in treating certain Gram-negative bacterial infections, it has been shown that parenteral administration of colistin (as its inactive prodrug colistin methanesulphonate) and polymyxin B can be potentially nephrotoxic in up to 60% of patients, which limits them from being used more routinely to treat MDR Gram-negative infections. Furthermore, since nephrotoxicity is the major dose-limiting factor for the currently available polymyxins, suboptimal dosing of polymyxins can promote the emergence of polymyxin resistance. Accordingly there exists a need to develop novel polymyxin compounds that provide similar or better efficacy as the clinical available polymyxins but without the nephrotoxic side effects.